Incyte (INCY) investor relations material

Program Overview and Clinical Rationale

• INCA033989 is a first-in-class monoclonal antibody targeting mutant calreticulin (mutCALR) in myeloproliferative neoplasms (MPNs), specifically myelofibrosis (MF) and essential thrombocythemia (ET), aiming to shift therapy from symptom management to potential disease eradication.

• CALR mutations are present in 25–35% of MF and ET patients, with Type 1 being most common; current therapies do not target these mutations.

• INCA033989 disrupts the mutant CALR-TPO receptor complex, leading to internalization and degradation, selectively inhibiting oncogenic signaling and cell proliferation.

• The agent received FDA Breakthrough Therapy Designation for essential thrombocythemia with Type 1 CALR mutation in December 2025.

• The program aspires to provide targeted therapies for all MPN patients by the end of the decade.

Clinical Efficacy and Safety Data

• INCA033989 was well tolerated as monotherapy and in combination with ruxolitinib, with no dose-limiting toxicities or maximum tolerated dose identified up to 2,500 mg.

• Over 85% of patients remained on therapy at data cutoff, and discontinuation due to adverse events was low.

• Monotherapy in MF achieved SVR25 in 42% and SVR35 in 33% at week 24; combination therapy achieved SVR25 in 50% and SVR35 in 47% at best response.

• Symptom improvement was seen in 93% of monotherapy and 81% of combination patients, with up to 60% achieving ≥50% reduction in total symptom score.

• Anemia response occurred in 56% of evaluable anemic patients, with hemoglobin improvement and transfusion independence observed in some.

Molecular and Translational Insights

• Most patients experienced reductions in mutCALR variant allele frequency (VAF), with deeper reductions at higher doses and in those with spleen response.

• Therapy led to decreases in mutant stem and megakaryocyte populations, recovery of wild-type hematopoiesis, and improvements in bone marrow fibrosis.

• Clinical responses were associated with rapid reductions in mutCALR clone burden, even in patients with high-risk co-mutations.

• VAF reduction is a lagging indicator, but early reductions in stem/progenitor cells and increased erythroid progenitors suggest disease modification.

• Disease-modifying activity was demonstrated by reductions in mutCALR-positive cells and improvements in marrow structure.